U.S. patent application number 12/674745 was filed with the patent office on 2011-06-02 for stamper for microneedle sheet, production method thereof, and microneedle production method using stamper.
This patent application is currently assigned to BIOSERENTACH CO., LTD.. Invention is credited to Kenshin Honda, Masashi Motoi, Kanji Takada.
Application Number | 20110127690 12/674745 |
Document ID | / |
Family ID | 43857779 |
Filed Date | 2011-06-02 |
United States Patent
Application |
20110127690 |
Kind Code |
A1 |
Honda; Kenshin ; et
al. |
June 2, 2011 |
Stamper For Microneedle Sheet, Production Method Thereof, And
Microneedle Production Method Using Stamper
Abstract
Microneedle sheets are produced by injecting a needle raw
material into a stamper formed with a concavity in a base material.
However, it was not easy to increase the degree of sharpness of the
concavity which corresponds to the stamper tips. A method for
producing a stamper including the steps of heating a sheet-like
base material and an original plate having a conical protrusion,
inserting the protrusion of the original plate into the base
material to form a conical concavity in the original plate, cooling
the original plate with the original plate still inserted in the
base material, releasing the original plate from the base material,
and heating the base material.
Inventors: |
Honda; Kenshin; (Shiga,
JP) ; Motoi; Masashi; (Shiga, JP) ; Takada;
Kanji; (Kyoto, JP) |
Assignee: |
BIOSERENTACH CO., LTD.
Kyoto
JP
|
Family ID: |
43857779 |
Appl. No.: |
12/674745 |
Filed: |
January 15, 2010 |
PCT Filed: |
January 15, 2010 |
PCT NO: |
PCT/JP2010/050409 |
371 Date: |
October 14, 2010 |
Current U.S.
Class: |
264/154 |
Current CPC
Class: |
A61M 2037/003 20130101;
A61M 2037/0053 20130101; A61M 37/0015 20130101; B29C 59/02
20130101; A61M 2037/0046 20130101 |
Class at
Publication: |
264/154 |
International
Class: |
B29C 67/00 20060101
B29C067/00; B29C 35/02 20060101 B29C035/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 8, 2009 |
JP |
2009-234110 |
Claims
1. A method for producing a stamper comprising the steps of:
heating a sheet-like base material and an original plate having a
conical protrusion; forming a conical concavity by inserting the
protrusion of the original plate into the base material; cooling
the original plate with the original plate still inserted in the
base material; releasing the original plate from the base material;
and heating the base material.
2. The method for producing a stamper according to claim 1,
wherein, in the step of forming a conical concavity, the protrusion
of the original plate is inserted into the base material until the
protrusion penetrates the base material.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for producing a
female mold to produce a microneedle for injecting a drug from a
skin.
BACKGROUND ART
[0002] A microneedle sheet is a sheet in which very small needles
having a length of about 1 .mu.m to 600 .mu.m, and a high aspect
ratio of the cross-sectional diameter at the base to the length of
cross-sectional diameter:length=1:1.5 to 1:3, are arranged at a
predetermined density onto a sheet substrate. The microneedle sheet
is used for injecting a drug by placing it against mainly a skin
portion of a human body, and inserting the microneedles
(hereinafter, sometimes referred to simply as "needle") into the
epidermis portion in the skin.
[0003] Since the microneedles have a length of about several
hundred .mu.m, they cause almost no pain or itchiness. Furthermore,
the microneedle portion is formed from a self-dissolving substance
so that when the sheet is removed from the skin there is no harm to
the body even if the microneedles remain in the skin.
[0004] A common method for producing a microneedle sheet will now
be described with reference to FIG. 5. An original plate 90 of a
microneedle sheet is produced by a method such as fine machining, a
vacuum treatment, or photolithography. As described above, the
needle has a length 93 of several hundred .mu.m or less, and has a
conical shape. The needle cross-section may be circular, angular,
elliptical or the like. Since the needle has a very small size, it
is preferred to form the needle 92 by shaving from an original
plate sheet 90.
[0005] Next, the original plate 90 is pressed against a stamper
base material 81 to produce a stamper 80 (a mold for a microneedle
sheet). Then, a resin polymer solution or a drug 85 is injected
into the stamper 80. The resin polymer solution or drug 85 is
dried, then stuck onto a fixing substrate 88 to be transferred
thereonto and peeled off from the stamper 80, whereby a microneedle
sheet 77 can be obtained (see Patent Document 1).
[0006] In the method for producing this stamper 80, rather than
pressing the original plate 90 against the base material 81, the
dissolved resin may be injected into the original plate 90, dried,
and then peeled off (see Patent Document 2).
LIST OF PRIOR ART DOCUMENTS
Patent Documents
[0007] [Patent Document 1] Japanese Patent Application Laid-Open
No. 2008-245955
[0008] [Patent Document 2] Japanese Patent Application Laid-Open
No. 2008-006178
[0009] [Patent Document 3] Japanese Patent Application Laid-Open
No. 2009-083125
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0010] For a microneedle to penetrate the skin, the tip of the
microneedle has to have a degree of sharpness which is as high as
possible. Furthermore, a microneedle sheet is produced by injecting
a needle raw material into a produced stamper. Therefore, the
bottom of a concavity of the stamper into which the raw material is
injected (corresponding to the tip of the microneedle) has to be a
hollow with a high degree of sharpness. However, there has been the
problem that it is not easy to form a hollow having a high degree
of sharpness in the base material.
[0011] Furthermore, from the perspective of injecting the needle
raw material into the stamper, since the concavities in the stamper
have extremely small dimensions, there has been the problem that
the raw material of the microneedles is not easily filled into the
concavities of the stamper due to air and surface tension of the
material.
[0012] More specifically, in FIG. 5(c), when a resin polymer
solution or a drug 85 is injected into the stamper 81, air 72 is
present in a concavity of the stamper. When peeling from the
stamper, at a portion (73) where the air 72 was present, the needle
can only be formed in an incomplete shape (FIG. 5(d)).
[0013] This problem is also described in Patent Documents 2 and 3.
Patent Document 2 describes carrying out the filling of the raw
material into the stamper under a reduced pressure. Patent Document
3 describes filling a raw material into a stamper concavity while
applying a pressure from the raw material side. However, when
providing many microneedles, there is the problem that the raw
material is not filled in some of the concavities, which means that
not all of the planned microneedles can be formed.
Means for Solving the Problems
[0014] The present invention was created in consideration of the
above-described problems. Specifically, the present invention
provides a method for producing a stamper comprising the steps of:
[0015] heating a sheet-like base material and an original plate
having a conical protrusion; [0016] forming a conical concavity by
inserting the protrusion of the original plate into the base
material; [0017] cooling the original plate with the original plate
still inserted in the base material; [0018] releasing the original
plate from the base material; and [0019] heating the base
material.
[0020] Furthermore, the method for producing a stamper according to
the present invention is characterized in that, in the step of
forming a conical concavity, the protrusion of the original plate
is inserted into the base material until the protrusion penetrates
the base material.
Advantages of the Invention
[0021] In the present invention, a conical concavity is provided by
inserting an original plate having a conical protrusion into a
warmed stamper member. The original plate is cooled in that state,
and then released from the stamper member. Therefore, the concavity
is formed with stress still remaining in the stamper member which
was deformed by the conical protrusion. If the stamper member is
heated after releasing the conical protrusion, the stress is
released, and re-deformation occurs so that the concavity is filled
in. Consequently, the base material is re-deformed in a direction
in which the bottom of the concavity is narrowed, and this enables
a concavity with a high degree of sharpness to be formed.
[0022] Furthermore, if a through-hole which penetrates as far as an
opposite face of the stamper is formed in the bottom of the
concavity in advance, and the stamper member is re-deformed by the
above-described method, a very small through-hole can be formed.
The concavities of the stamper having very small through-holes
allow air to easily escape even if air accumulates during the
coating of the microneedle member. Consequently, a microneedle
sheet can be obtained on which all of the planned microneedles are
formed by enabling a raw material to be filled into all of the
concavities of the stamper.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a schematic diagram of a stamper according to the
present invention.
[0024] FIG. 2 is a diagram illustrating a production process of the
stamper according to the present invention.
[0025] FIG. 3 is a diagram illustrating the production process of
the stamper according to the present invention in detail.
[0026] FIG. 4 is a diagram illustrating a production process of a
microneedle sheet using the stamper according to the present
invention.
[0027] FIG. 5 is a diagram illustrating a production process of a
microneedle sheet using a conventional stamper.
BEST MODE FOR CARRYING OUT THE INVENTION
Embodiment 1
[0028] FIG. 1 illustrates a stamper 1 of a microneedle sheet
according to the present invention. The stamper 1 is formed with
conical concavities 3 in a sheet-like base material 2. The material
of the base material 2 is not especially limited. However,
considering that such a material will be used together with a
medicine, a material which does not easily contaminate or does not
have an effect on the human body is preferred. Furthermore, the
stamper 1 according to the present invention forms a concavity
shape having a tip with a high degree of sharpness by thermal
shrinkage. Therefore, it is preferred to use a plastic such as
PTFE, polypropylene, and polyethylene.
[0029] A through-hole 4 which penetrates to another face of the
base material is formed in each of bottom portions of the
concavities 3. The through-hole 4 preferably has a small diameter,
because the through-hole 4 will act as the portion which forms the
tip of the microneedle. Functionally, the through-hole 4 does not
have to be a hole with a finite diameter which is constantly open,
so long as air which has accumulated in the concavity can escape in
order for the raw material to be filled into the concavities 3.
Specifically, as long as air escapes when a pressure is applied,
the through-hole may normally look like it is closed. More
specifically, the through-hole preferably has a diameter of several
tens of microns or less.
[0030] The microneedle arrangement density and arrangement
distribution are not especially limited, and these may be
determined as necessary based on the application and purpose. In
the drawings, for simplicity, a stamper for producing a microneedle
sheet having four microneedles is illustrated.
[0031] Next, examples of the method for producing the stamper
according to the present invention will be described. With
reference to FIG. 2(a), an original plate 10 includes a flat body
11 on which conical protrusions 12 are formed. The material for the
original plate 10 is not especially limited, but it is preferred to
use a metal which has excellent workability. Furthermore, in the
present invention, the base material is heated to a temperature
near its softening point. Therefore, a material capable of
maintaining hardness at around that temperature is preferred. Since
the conical protrusions are very small, a material which can be
easily shaved is preferred. Examples of the material used include
copper, aluminum, nickel, silicon and the like. In addition to the
processing of the protrusions 12 by shaving the protrusions from
the body 11, the protrusions 12 may also be formed by a method
using photolithography.
[0032] The protrusions 12 stand on the body 11 with a height 13 of
from about 1 .mu.m to 600 .mu.m. The reason for the height setting
is as follows. Although the epidermis into which the drug or the
like is injected using the microneedle sheet is formed from the
stratum corneum, stratum granulosum, stratum spinosum, and stratum
basale, the thickness of the stratum corneum is different depending
on the area of the body. Thus, the height of the microneedles can
change depending on the area of the body into which transdermal
administration is to be carried out and the drug.
[0033] The protrusions 12 have a needle shape with a comparatively
high aspect ratio of the cross-sectional diameter at the base of
the microneedle formed by the stamper to the length of
cross-sectional diameter:length=1:1.5 to 1:3. This is because the
microneedles may change depending on the area to be used. The
cross-sectional shape is not especially limited. Examples of shapes
which may be preferably used include circular, elliptical,
rectangular including square, and the like. Furthermore, a groove
may be formed on the surface of the protrusions. This is because a
microneedle which reflects the shape of such a groove can be
smoothly inserted into the skin.
[0034] A thickness 5 of the base material 2 is thinner than a
length 13 of the protrusions 12. The tip of the protrusions 12 is
for penetrating the base material 2 to form the through-hole 4. The
diameter of the through-hole 4 formed in the base material 2 can be
set based on the tip shape of the protrusions 12 and the thickness
5 of the base material 2 so as to be about several tens of microns.
This is because, in the present invention, the through-hole 4 may
be shrunk by thermal shrinkage, which means that a through-diameter
4a formed when a protrusion 12 of the original plate 10 penetrates
the base material 2 may be several times larger than the
through-hole 4 of the stamper 1.
[0035] First, the original plate 10 and the base material 2 are
subjected to pre-heating 14. The heating temperature is a
temperature lower than the melting point of the base material 2.
The heating temperature is preferably near the softening point
temperature of the base material 2. This is because in the
formation of the concavities of the stamper according to the
present invention, a step of causing plastic deformation with
stress remaining in the base material 2 is carried out. If the
temperature of the original plate 10 is higher than the melting
point of the base material 2, the base material 2 melts, so that
the concavities 3 cannot be formed in the shape of the protrusions
12 of the original plate 10. Furthermore, if the temperature of the
original plate 10 is too low compared with the temperature of the
base material 2, the stress which is required during the
re-deformation does not remain.
[0036] Next, the heated original plate 10 is thrust into the heated
base material 2 (FIG. 2(b)). Then, with the original plate 10 still
stuck in the base material 2, the original plate 10 is cooled to
room temperature, and then released from the base material (FIG.
2(c)). FIG. 3(a) illustrates an enlarged view of a portion where
the protrusion 12 of the heated original plate 10 was thrust into
the heated base material 2. At the potion where the protrusion 12
is inserted into the base material 2 (reference numeral 26), the
base material is pushed wider by the protrusion 12. Consequently,
the molecules are in a compressed state. This compressed portion is
referred to as a "concavity surface layer 26".
[0037] With reference to FIG. 3(b), when the cooled original plate
10 is released, the shape is maintained in a state in which the
stress 27 is still accumulated in the concavity surface layer 26
having the through-hole. In FIG. 3(b), while a reference numeral
was given for the two arrows on the left and right, the other
arrows also represent stress. Further, the through-hole which is
formed at this stage is the through-hole 4a.
[0038] Returning to FIG. 2(d), after the cooling, the base material
2 from which the original plate 10 was released is re-heated. The
heating temperature at this stage is near the softening point
temperature thereof, and preferably at or lower than the melting
point thereof. This is because if the heating temperature is in
this range, deformation can occur due to the release of stress in
the concavity surface layer.
[0039] With reference to FIG. 3(c), since the stress is released at
the concavity surface layer of the heated base material 2, the
surface layer moves toward (28) a free space. As a result of the
re-deformation due to this thermal shrinkage, the through-hole
shrinks, whereby a concavity having a high degree of sharpness can
be formed. Furthermore, compared with a case when the original
plate of FIG. 3(b) was released, a through-hole diameter (4a.phi.)
decreases (4.phi.) due to the shrinkage. More specifically, for an
example of a polyethylene base material 2, if the base material 2
is held at 90.degree. C. for about 10 seconds, the diameter of the
through-hole can be shrunk from 40 .mu.m to 10 .mu.m, so that a
very small microneedle can be produced.
[0040] The microneedle sheet is produced using the thus-produced
stamper. With reference to FIG. 4, the microneedle sheet is
produced by coating a needle raw material 20 on the stamper 1 (FIG.
4(a)). As the needle raw material 20, it is preferred to use a
material which is discharged without remaining in the body. The
reason for this is as follows. When the microneedle sheet is peeled
off from the skin, the needle portions may break or be pulled out
of the sheet, so that some needles cannot be recovered. Therefore,
in such cases, it is safer if the material is absorbed by the body.
Specifically, the needle raw material is preferably a material
which has a thread-forming substance and the like as a main
component. It is also preferred to pre-mix the drug in the needle
raw material. Here, the term "drug" refers to a pure chemical
substance having a physiologically active effect. Examples of such
a substance include peptide/protein drugs such as insulin, growth
hormone, erythropoietin, and interferon, polymer drugs, vitamin C
and the like. The drug may also be a substance having any one of
them as a main component.
[0041] As illustrated in FIG. 4(a), the stamper 1 according to the
present invention has the through-holes 4 formed in the bottoms of
concavities 3. Therefore, to inject the needle raw material into
the stamper, the needle raw material is filled into the concavities
just by coating. Specifically, even if air 72 is present at the
bottoms of the concavities 3 of the stamper 1, the air can easily
be discharged via the through-holes 4, so that the needle raw
material is filled into the concavities 3. Obviously, a pressure 15
may be applied after the coating (FIG. 4(b)). If a pressure is
applied, air which has accumulated at the bottoms of the
concavities 3 of the stamper can easily escape.
[0042] Furthermore, the stamper 1 may be arranged on a flat mount
18 formed by a porous solid, and the needle raw material 20 can be
coated while applying a negative pressure 16 from the back face of
the flat mount 18 (see FIG. 4(b)). In this case too, the needle raw
material 20 can be easily injected into the concavities 3 of the
stamper. Moreover, it is more preferred to apply a pressure 15 from
the top face of the flat mount 18 and apply the negative pressure
16 from the back face.
[0043] After the needle raw material 20 is coated on the stamper 1,
the needle raw material 20 is dried and peeled from the stamper,
thereby completing a microneedle sheet 30 (see FIG. 4(3)). The
peeling from the stamper 1 is carried out by sticking the fixing
substrate 88 from the back face of the dried needle raw material
20, and peeling from the stamper. If a drug was not added into the
microneedle sheet 30 peeled from the stamper, after being peeled
from the stamper, the drug is dispersed or the like in a needle
portion 31.
[0044] Furthermore, the thus-produced microneedles 31 are formed in
a conical shape having a comparatively high aspect ratio in which
the ratio of the cross-sectional diameter at the base of the
microneedle 31 to the length thereof is cross-sectional
diameter:length=1:1.5 to 1:3.
[0045] Thus, in the stamper according to the present invention, a
very small through-hole which penetrates as far as an opposite face
of the stamper is drilled into the bottom of a concavity forming a
needle. Therefore, even if air is in the concavity, the air can
easily escape, which allows a microneedle sheet that can produce a
needle having a high degree of sharpness to be obtained.
INDUSTRIAL APPLICABILITY
[0046] The present invention can not only be used for a microneedle
sheet which injects a drug into the epidermis, but can also be
widely used as a method for generating very small protrusions on a
substrate.
DESCRIPTION OF REFERENCE NUMERALS
[0047] 1 stamper
[0048] 2 base material
[0049] 3 concavity
[0050] 4 through-hole
[0051] 5 thickness of base material
[0052] 10 original plate
[0053] 11 body of original plate
[0054] 12 protrusion
[0055] 13 height of protrusion
[0056] 14 heating
[0057] 15 pressure
[0058] 16 negative pressure
[0059] 18 flat mount made of porous solid
[0060] 20 needle raw material
[0061] 26 concavity surface layer
[0062] 27 stress
[0063] 28 moving direction of concavity surface layer
[0064] 30 microneedle sheet
[0065] 31 needle
[0066] 72 air
[0067] 77 microneedle sheet
[0068] 80 conventional stamper
[0069] 81 conventional stamper base material
[0070] 85 needle raw material
[0071] 88 fixing substrate
[0072] 90 original plate
[0073] 91 body
[0074] 92 protrusion
[0075] 93 length of protrusion
* * * * *